We will continue our study of genes needed for neuronal differentiation and function using the six touch receptor neurons (TRNs) in the nematode Caenorhabditis elegans. Previous research under this grant identified genes needed for the generation, specification, maintenance and function of the TRNs. In the last funding period we 1) identified genes needed for the specification of neuronal subtypes; 2) discovered a new activity (refinement) that maintains transcription factor expression by the restricting its stochastic expression; 3) examined the how the release of epigenetic inhibition affects the terminal differentiation of subtypes of motor neurons; 4) discovered several behaviors that modulate TRN touch sensitivity, including a previous unstudied type - long-term sensitization - and the mechanisms underlying these modulations; 5) identified a role for integrins and other focal adhesion proteins in neuronal mechano- sensation; 6) discovered that the alpha-tubulin acetyltransferase MEC-17 specifies the unusual, 15-protofilament structure of TRN microtubules; and 7) discovered a microtubule-based regulation of general cellular transcription/translation and the genes needed for it. We also introduced a method for feeding RNAi in neurons. We began successful mutageneses to obtain mutants defective in neuronal outgrowth and neuronal ensheathment, devised a new method to characterize habituation, and used this method to identify genes needed for habituation. The general goal of the research described in this proposal is to exploit these findings and methods to understand how the differentiation of individual cell types is controlled and how mechanical inputs are sensed and modified. The specific aims of the proposal are 1) to discover and characterize genes needed for TRN differentiation, specifically those needed for the differences among TRNs and TRN process outgrowth and ensheathment; 2) to investigate touch sensitivity and its control by investigating newly identified lethal genes needed for touch sensitivity and testing and characterizing TRN-expressed genes for supersensitivity; and 3) to characterize modulation of touch sensitivity, including habituation. The health relatedness of our work comes from the discovery of new genes and new interactions among genes that are similar in humans and other mammals.